A variety of organisms settle and colonize surfaces exposed to aquatic environments. These include bacteria, algae and sedentary invertebrates such as bryozoans, sponges, mollusks and barnacles. For example, barnacle larvae are major biofouling animals on marine surfaces. Encrusted barnacle populations increase the fuel requirements for ships, slow their passage and cause deterioration of the painted surface leading to corrosion.
Until now, efforts to inhibit the settlement of aquatic organisms have focused primarily on the inclusion of organotin paint additives that are toxic to a wide variety of aquatic organisms. With this strategy, the exposed surface must be scrapped and repainted at frequent intervals. Also, although organotin additives to marine paints are effective anti-fouling agents, unfortunately they also damage the marine environment, killing and sterilizing many free-living organisms where vessels are docked. The consequent pollution of harbors and coastal marine waters led to a ban on the use of such additives starting in 2003. Safer new antifouling additives are urgently needed to replace these toxic additives. Thus, there is much interest in finding new materials and methods to inhibit the colonization of surfaces by marine and other aquatic organisms.
It would be highly desirable to have anti-fouling additives that are more selective and more easily degraded such that they are less toxic. As the field evolves towards more selective and less toxic additives, one approach might be to exploit mechanisms associated with the process of settlement rather than with a broad spectrum biocide.
Little is known about the chemoreceptive capabilities of barnacle larvae, although knowledge of the chemoreceptors of other crustaceans is more advanced (Strausfield, N., Hildebrand, J. [1999] Curr. Rev. Neurobiol. 9:634–639). Besides being receptive to amino acids, some decapod crustacean neuronal chemoreceptors are sensitive to certain pyridine compounds, especially 3-substituted pyridines (Hatt, H., Schmiedel-Jakob I. [1984] J. Comp. Physiol. 154A:855–863; Hatt, H., Schmiedel-Jakob I. [1985] Chem. Senses 10:317–323; Schmiedel-Jacob I., Breuninger V., and Hatt H. [1988] Chem. Senses 13:619–632). Some of the most potent 3-pyridyls are natural toxins found in certain nemertines, a phylum of nearly 1,000 recorded species of carnivorous flatworms (Gibson, R. Nemerteans. London: Hutchinson University Library, 1972). Bacq (Bacq, Z. (1936) Bull. Acad. R. Belg. Cl. Sci. (Ser 5) 22:1072–1079) first demonstrated that nemertines possess toxins. Several decades later the alkaloid anabaseine (FIG. 1A) was isolated from a hoplonemertine (Kem W., Abbott, B., Coates, R. (1971) Toxicon. 9:15–22). Nemertines belonging to this taxonomic class were subsequently found to contain a variety of pyridyl alkaloids besides anabaseine (Kem, W. (1971) Toxicon. 9:23–32; Kem, W., Scott K., and Duncan J. (1976) Exper. 32:684–686; Kem, W. (1988) Hydrobiolog. 156:145–147; Kem, W. (2002) In: Handbook of Neurotoxicology, E. J. Massaro, Ed. Vol. 1. Humana Press, Totowa, N.J., pp. 161–193). 2,3′-bipyridyl (BP) was identified as the major toxic constituent of the chevron nemertine Amphiporus angulatus, a circumboreal species found along northern Atlantic and Pacific coastlines (Kem, W., Scott K., and Duncan J. (1976), supra; Kem, W., Soti, F. (2001) Hydrobiolog 456:221–231). The worm uses its armed proboscis to mechanically capture and chemically paralyze its arthropod prey.
2,3′-BP (FIG. 1B) is the only bipyridyl that has been found in living organisms, namely tobacco plants and A. angulatus. However, 2,2′-BP, because of its ability to chelate certain heavy metals, is the most widely known BP. It is an important industrial product. The insecticidal activity of 2,3′-BP was noticed many decades ago, but apparently it was never marketed as an insecticide (Smith, C., Richardson, D., Shepard H. (1930) J. Econ. Entomol. 23:863–867). Some of the methyl-bipyridyls have been found in tobacco leaves and/or tobacco smoke. The 5-methyl-2,3′-bipyridyl was found in cured Nicotiana tabacum leaves (Warfield, 1972; Matsushima, 1983) as well as in cigarette smoke. The 6- and the 2′- (or 3-) methyl-2,3′-bipyridyls were also found in cigarette smoke (Schumacher et al., 1977; Sakuma et al., 1984; Heckman and Best, 1981).
Five methyl-2,3′-bipyridyls, including the 4- and 5-methyl-2,3′-bipyridyls, have been synthesized by the condensation of pyridine-3-diazonium chloride with either 4-methylpyridyl or 5-methylpyridyl (Frank and Crawford, 1959; Warfield et al., 1972), or by palladium catalyzed cross-coupling reactions (Ishikura et al., 1984; Bloom, 1990; Jacob et al., 1993). The 6-methyl-2,3′-bipyridyl has also been prepared by the latter methods. The 3-, 5- and 2′-methyl-2,3′-bipyridyls have been prepared by catalytic dehydrogenation in gas phase (Bowden, 1969). However, until the practice of the subject invention, the synthesis of 4′-, 5′, and 6′-methyl-2,3′-bipyridyls had not been reported.